SUMMARY?PROJECT 2: NEUROPATHOLOGY OF AMYLOID AND TAU. The presence of neurofibrillary tangles (NFT) in the entorhinal cortex (EC), a nodal point of cortico-hippocampal circuits, is not only a constant feature of the earliest pathological stages of Alzheimer's disease (AD) but also a nearly universal finding at autopsy in clinically normal elders. Two very different possible fates can be imagined: All individuals who harbor NFT in the EC (e.g., Stages I-II according to Braak and Braak staging) are inevitably destined to exhibit spreading of tau pathology to other brain regions and to develop symptoms of dementia given enough time; or a proportion of them have specific features in their brains that render them less vulnerable to the neurotoxic effects of AD pathology, and they will remain asymptomatic. We will test a model in which tau mislocalization to the synaptic compartment underlies synaptic loss, and release of tau at the synapse that is the substrate of NFT propagation across the cortex. The recent development of novel PHF-tau targeting PET tracers, such as T807, tailored to allow in vivo detection of NFT and related phosphotau pathologies, represents a unique opportunity to test this model, and to shed light on the fundamental question of how to interpret the presence of NFT in the EC. This project has been designed to: 1) validate T807-PET in postmortem human brain, to best understand exactly what T807 ligand retention implies at a cellular and molecular level. Specifically, we will test the idea that novel T807 ligand targets NFT as well as abnormal neuritic and synaptic accumulations of hyperphosphorylated tau; and 2) identify associated anatomical and biochemical abnormalities that may differentiate individuals who have both NFT and synaptic and neuronal loss, and appear to be in the earliest stages of AD, from those who develop NFT but are resilient to neuronal, synaptic, and glial responses that can accompany the presence of tangles in the EC. We will test the proposal that the presence of amyloid deposits impacts tau accumulation in neurites and hence in progression. A further prediction of this model is that selective accumulation and mislocalization of soluble oligomeric tau into the synapses in the hippocampus and other potential nodes of synaptic vulnerability, like posterior cingulate and fusiform/inferior temporal gyri, correlate with loss of neural system integrity. Importantly, these molecular and cellular correlates of NFT in EC can be examined only at autopsy. We have begun to examine this model in cases available from the MADRC Brain Bank, and will do so in HABS cases that come to autopsy, but realize that cases of well-characterized controls coming to autopsy may be few. We therefore propose to utilize the very well-characterized Rush cohorts (population based cohorts of independently living individuals with nearly 100% autopsy rates and longitudinal clinical evaluations) so that we are assured of being able to select cases that match the clinical characteristics of HABS subjects. This program will develop the data necessary to guide interpretation of tau neuroimaging in clinical settings and to define rational targets for future effective therapeutic interventions.